Atherosclerosis and its clinical consequences, coronary heart disease (CHD), stroke and peripheral vascular disease, represents a truly enormous burden to the health care systems of the industrialized world. In the United States alone, approximately 13 million patients have been diagnosed with CHD, and greater than one half million deaths are attributed to CHD each year. Further, this toll is expected to grow over the next quarter century as the average age of the population increases and as an epidemic in obesity and diabetes continues to grow.
Inhibition of cholesteryl ester transfer protein (CETP) is a promising new approach to reducing the incidence of atherosclerosis. Statins have been important in reducing the incidence of CHD by reducing LDL-cholesterol (the “bad cholesterol”), but are relatively ineffective at raising HDL-cholesterol (“the good cholesterol”). CETP inhibitors raise HDL-cholesterol and may also lower-LDL-cholesterol, and may therefore provide a potent new tool for reducing CHD and atherosclerosis in the general population. Combination therapy using CETP inhibitors and statins may also become a valuable tool for controlling both HDL and LDL levels, which may make it possible to both treat and prevent atherosclerosis, and perhaps even to reverse the formation of atherosclerotic plaques. Pfizer's torcetrapib was withdrawn from Phase III clinical trials because it showed an increase in mortality in the group taking the drug compared with the control group in a long-term outcomes study. The cause of the increased mortality has not yet been determined, and the mechanism has so far not been blamed for the increase in mortality.
CETP inhibitors in general are very lipophilic. The compounds are generally nearly insoluble in water and in aqueous bodily fluids. Bioavailability of CETP inhibitors using conventional tablet formulations often is poor. Oral formulations therefore need to be developed that will make the compounds more readily bioavailable when they are administered to a patient. Furthermore, many conventional formulations comprising highly insoluble lipophilic compounds, such as the CETP inhibitors used herein, show a significant “food effect,” where there is a large difference in the amount and rate of absorption into the body depending on when the patient was last fed before oral administration of the drug and whether the patient takes the drug with a meal. In general, a significant difference is observed in absorption after oral administration depending on whether the patient is in a fasted state and also on when and what the patient has eaten if the patient is not in a fasted state. Several approaches to improving bioavailability have been proposed in the patent and non-patent literature. These approaches include emulsions, microemulsions, emulsion and microemulsion preconcentrates, also known as self-emulsifying drug delivery systems (SEDD's) and self-microemulsifying drug delivery systems (SMEDD's), nanoparticles, and amorphous dispersions in a carrier. Solid formulations which are amorphous dispersions of a particularly potent class of CETP inhibitors in which the compound is dissolved or dispersed in a polymer in a non-crystalline state are described herein.